Questions and answers
The mutation that causes DBA can be inherited from a parent or may occur at an early stage of the embryo. As with many other illnesses, it is not yet known what causes or triggers the onset of these new mutations.
The mutations always affect all body cells and can be passed on to offspring. There is a 50% chance of passing on a DBA mutation to the next generation. This form of inheritance is called “autosomal-dominant” since inheriting a DBA mutation from just one parent is enough to trigger the disease in offspring.
Where several members of a family are affected by DBA they all have the same causal mutation. However the DBA symptoms of the family members affected may differ widely, ranging from no health problems at all to requiring transfusions. The reason for the differences in the presentation of the disease is largely unknown. Although generally the severity of DBA increases from generation to generation (“anticipation”), it is not possible to predict the severity of the disease for the individual carrier of a DBA-typical mutation.
All patients with DBA should be offered genetic counselling. Prenatal diagnostic testing (genetic diagnostic testing before birth) and pre-implant diagnostic testing (for in vitro fertilisation/artificial insemination) to identify a known DBA mutation in a parent are possible, but cannot predict the presentation and severity of the disease.
The health problems of patients with DBA are mainly due to decreased haematopoiesis in the bone marrow and the treatment this requires. Decreased erythropoiesis (the production of red blood cells) causes anaemia; in rare cases it also causes a decrease in the production of leukocytes (white blood cells) and/or thrombocytes (platelets). Associated malformations may require corrective surgery. Patients with DBA have an increased cancer risk. The level of this risk and its significance cannot currently be clearly stated. Organ damage may occur as a result of treatment for anaemia with blood transfusions. In the liver, the pancreas and myocardium in particular, damage may occur as a result of iron overload from blood transfusions; iron overload may also occur in non-transfused patients.
The blood system
Red blood cells, white blood cells and platelets are produced in the bone marrow. DBA can lead to decreased production in all three lineages (“pancytopenia”). Decreased erythropoiesis and the anaemia it causes are the main symptoms in almost all cases. The white blood cell count is slightly depressed in many DBA patients without any impact on their health.
Typical symptoms reported by patients with anaemia are increased pallor, palpitations, headache, fatigue, shortness of breath during physical exertion as well as poor appetite and failure to thrive in infants. Although infants in particular often appear to be relatively unaffected despite clearly being anaemic it is likely that anaemia will have an unfavourable impact on a DBA patient’s health in the long term. DBA patients should therefore be given consistent treatment for anaemia at every year of life.
Possible malformations
Around 40% of DBA patients have congenital malformations that can affect various different organs. Common malformations are those affecting the face, such as a cleft palate, or arms and the thumb. Heart defects, kidney deformities, inguinal hernias, congenital glaucoma or cataract, skin lesions such as large “liver spots” and developmental disorders may occur. Body length is at the lower end of the normal range for most DBA patients, with restricted growth in some patients.
Infants with DBA have been described as having a typical “DBA facies” with a snub nose, widely-spaced eyes, thick upper lip, deep-set ears and an alert expression. However these abnormalities appear to vanish as infants grow.
On the cancer risk
DBA patients have a higher risk of developing cancer in the course of their lifetime compared with their healthy peers. Currently it is not possible to provide an adequate assessment of the precise level of risk. In contrast to other congenital bone marrow disorders such as Fanconi anaemia, severe congenital neutropenia, Shwachman-Diamond syndrome, recent data reveal no increase in, or only a slightly increased, risk of the onset of leukaemia or a myelodysplastic syndrome (MDS). However, reports of diseases such as breast cancer, bowel cancer or other carcinomas have increased in recent years in young and middle aged DBA patients.
The data situation is currently not good enough to develop a general recommendation on the need for a cancer screening programme for DBA patients. Annual health check-ups by the GP or specialist, take-up of health screening and care measures available to the public and consulting a doctor if symptoms occur (diarrhoea, blood in stools, chest pain, changes in moles etc.), however, are explicitly recommended for all DBA patients, particularly in adulthood. Case reports show an increase in incidence of bone tumours (osteosarcoma) in children, adolescents and young adults, however early detection of these cancers is not currently possible.
Organ damage due to iron overload
Red blood cells transport oxygen in the blood. They contain haemoglobin which binds the oxygen via an iron molecule. The body responds to anaemia by attempting to increase erythropoiesis by, for example, increasing iron absorption from food in the gut. However, patients with DBA cannot metabolise this additional iron intake since haematopoiesis is impaired due to the ribosomal malfunction. Since the human body does not have a mechanism for eliminating the surplus iron, patients with DBA may develop iron overload spontaneously. The iron cannot be metabolised and is stored in the organs. Blood transfusions, which consist of red blood cells, add to the iron overload since red blood cells contain large amounts of iron.
Long-term iron overload causes damage to many organs, in particular the heart, liver and various hormone-producing glands such as the thyroid gland, the pituitary gland and the pancreas. Without adequate treatment, therefore, severe (sometimes fatal) complications may occur such as myocardial insufficiency and cardiac arrhythmias (cardiomyopathy), hepatitis and liver dysfunction, diabetes, restricted growth, delayed puberty, hypothyroidism and disorders of Vitamin D metabolism.
DBA patients with iron overload and/or patients regularly receiving blood transfusions are therefore given treatment with drugs that combine with the surplus iron so it can be eliminated via stools and urine.
Treatment of patients with rare forms of anaemia should be carried out by an experienced centre for blood disorders. Regular tests should be performed at the centre to measure the iron overload and screen for potential complications of the iron overload. Early identification of complications considerably improves the chances of a successful treatment outcome. We have produced a checklist of the regular tests recommended for DBA patients (see Download section).
The human body cannot eliminate excess iron itself. Drug treatment to help flush the iron out of the body (iron chelation therapy) is therefore required. This uses chelators, substances that bond with the surplus iron to form a compound (chelate). The bonded surplus iron can then be excreted via urine and/or stools. Treatment should start after ferritin readings reach a specific level (in most cases 2 x readings >1000 ng/mL), the iron load in the liver tissue reaches a specific level (in most cases > 4.5 mg iron/g of dry weight of liver) or after approximately 10 - 15 transfusions. The international recommendation is that iron chelation therapy should not begin before the 2nd birthday.
There are currently three different iron chelators in use: deferoxamine (DFO, brand name Desferal®), deferasirox (DSX, brand name Exjade®) and deferipron (DFP, brand name Ferriprox®). Deferoxamine may be injected in three ways: through the skin (subcutaneously), muscle (intramuscular) or vein (intravenously). Deferasirox can be swallowed by patients as a tablet or ground powder (oral chelator). The oral chelator Deferipron is available for a few patients with DBA for whom treatment with Deferoxamin or Deferasirox is not an option. Which of the different chelators is used depends on age, individual side effects and of course how effective the drugs are in treating the iron overload in the various organs. Very intensive iron chelation measures may be required in patients with very severe iron overload and heart failure, cardiac arrhythmias or diabetes. In conclusion, iron chelation therapy should only be controlled and monitored by a specialist in blood disorders. We have produced a checklist of the additional regular tests recommended for patients undergoing iron chelation therapy (see Download section).
The quality of medical care provided has a huge effect on the prognosis for patients with DBA. Age-appropriate patient consultations, along with the opportunity for patient and relatives to be involved in care, play an important role here.
Almost all patients with Diamond-Blackfan anaemia (DBA) can successfully attend nursery and school, complete education or study, learn and practise a profession. Some patients (20-30%) even experience remission (where the anaemia spontaneously disappears) in the course of their life. The majority of patients, however, will permanently require steroid treatment or transfusions. The long-term prognosis for DBA patients may be restricted by complications from the transfusion therapy or excess doses of steroids. There is currently no way to assess how the increased cancer risk affects long-term survival rates.
It is yet not possible to predict how DBA will progress in individual patients. DBA may take an entirely unexpected course, even under the most favourable or unfavourable conditions. The overall life expectancy of DBA patients is not yet known. The disease was first described just 70 years ago and so there are not enough patients who have been observed over a long period. At the same time, there have been so many improvements in treatment over the last few decades (particularly treatment of iron overload) that the prognosis for all patients with congenital anaemia has improved considerably.
Since DBA is a highly complex disease there are numerous research questions that need an answer. The natural history of DBA is being recorded in numerous registers of DBA patients worldwide. Recording history in adult patients, their health and care status, as well as recording co-morbidities and cancers in later life form the focus of our current research. For this purpose we are currently developing a self-reporting online module that adult patients can use to submit their medical data themselves. We are currently learning from older DBA patients so that we can improve the therapy for young patients.
Even if a specific genetic alteration (pathogenic genetic variant) can be identified as disease causing in 70-80% of patients with clinical diagnosis of DBA, this still leaves a relevant proportion of patients for whom the alteration is yet to be identified. Identification of new pathogenic genetic variants causing DBA is being helped by the development of new functional tests that will allow DBA to be diagnosed even where there is no evidence of mutation. One possible method, but one not yet feasible for routine diagnostic testing, is human ribosome profiling. Ribosome profiles of patients with DBA are abnormal and differ from those of healthy human beings.
In order to understand how the disease disrupts haematopoiesis and why steroid therapy leads to remission of the anaemia in many but not all patients, the pathogenesis of DBA is being investigated in numerous laboratories around the world. One particularly important discovery was that the transcription factor GATA1, which is essential for erythropoiesis, cannot be produced properly as a result of the alteration of the ribosomes in DBA patients. Interestingly, patients with a congenital GATA1 mutation have a disease that is very similar to the classic form of DBA.
Since allogeneic stem cell transplantation continues to be the only curative treatment option for DBA patients, so that it is only the haematological problems and not other organ damage that can be treated, there is ongoing intensive research into other drugs for treating the disease. There are now large, highly IT-intensive platforms in existing that are searching for molecules that can restore ribosome function. Drugs that are approved for other diseases are also already undergoing testing on DBA patients in clinical trials, including elthrombopag in a US study.
With respect to allogeneic stem cell transplantation, clinical trials to identify the best time for and the best form of conditioning, i.e. preparatory chemotherapy prior to SCT, for DBA patients are underway.
As already mentioned in the “treatment methods for DBA patients”, the gene therapy in DBA patients with a pathogenic genetic alteration in the RPS19 gene is currently being developed. This initially requires in vitro experiments, although the principle of gene therapy for congenital anaemias has already been tested successfully in the form of Fanconi anaemia, a disease that can also be associated with abnormalities and bone marrow failure.